# Regulators of Immune Complex Mediated Neutrophil Recruitment and Tissue Injury

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $588,825

## Abstract

ABSTRACT
Antibody-antigen complex (IC) deposition within and outside blood vessels that is associated with
neutrophil infiltration is pathogenic in many human immune mediated disorders. The objective of this
competing renewal remains the delineation of receptors and intracellular signals that regulate IC-mediated
neutrophil recruitment and associated organ damage. FcγRs have emerged as key mediators of
inflammation in a range of IgG-mediated diseases from glomerulonephritis, arthritis and vasculitis to fatal
anaphylaxis. Our studies in mice expressing the uniquely human activating FcγR, FcγRIIA selectively on
neutrophils of mice lacking their own activating FcγRs have shown that FcγRIIA is a key molecular link
between IC deposition, neutrophil influx and tissue damage. As such, this receptor must be tightly
controlled. In the last funding cycle, we identified two major pathways regulating FcγRIIA function. First,
surprisingly, the neutrophil CD18 integrin Mac-1, known to promote inflammation, inhibited FcγRIIA
mediated neutrophil capture by immobilized ICs under flow by cis interaction of its ligand binding domain
with FcγRIIA's ectodomain. This may have relevance for human disease as the non-synonymous Mac-1
small nucleotide polymorphism (SNP) R77H associated with lupus and systemic sclerosis risk impaired
Mac-1's affinity for its known ligand, complement C3 and for FcγRIIA. Second, we showed that FcγRIIA
signaling to Abl-1/Src kinase and subsequent F-actin polymerization was required for rapid neutrophil
arrest on IgG and the strengthening of FcγRIIA-IgG bonds under shear flow in vitro. Accordingly, in vivo, 2-
photon intravital microscopy (IVM) of the kidney revealed that in glomerular capillaries, intravascular ICs
directly captured neutrophils via their FcγRIIA without evidence of prior neutrophil rolling. This recruitment
was inhibited by a Abl/Src inhibitor suggesting that it is an active process requiring intracellular signaling.
Two related questions arise from these findings that are the basis of the current proposal. First, how is the
interaction of FcγRIIA-Mac-1 ectodomains regulated, does R77H perturb this interaction and how does this
lateral interaction inhibit FcγRIIA affinity for ligand? Second, what FcγRIIA mediated intracellular pathways
are engaged to promote capture of circulating neutrophils by deposited IgG? These questions will be
addressed using knock-out mice, IVM and models of disease combined with fluorescent lifetime imaging
microscopy (FLIM) analysis, biochemical assays and in vitro assays that mimic neutrophil recruitment to
IC-coated endothelial cells under flow. We anticipate that the information provided by the proposed studies
will give insights into how FcγRIIA mediated neutrophil recruitment is regulated and thus identify important
therapeutic leads for the prevention of FcγRIIA mediated neutrophil accumulation, potentially one of the
earliest events in IgG mediated inflammatory disorders.

## Key facts

- **NIH application ID:** 9842323
- **Project number:** 5R01HL065095-21
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Tanya N Mayadas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,825
- **Award type:** 5
- **Project period:** 1999-09-30 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842323

## Citation

> US National Institutes of Health, RePORTER application 9842323, Regulators of Immune Complex Mediated Neutrophil Recruitment and Tissue Injury (5R01HL065095-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842323. Licensed CC0.

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